70918-54-6Relevant academic research and scientific papers
Investigation of the effect of different linker chemotypes on the inhibition of histone deacetylases (HDACs)
Linciano, Pasquale,Benedetti, Rosaria,Pinzi, Luca,Russo, Fabiana,Chianese, Ugo,Sorbi, Claudia,Altucci, Lucia,Rastelli, Giulio,Brasili, Livio,Franchini, Silvia
, (2020/11/24)
Histone Deacetylases (HDACs) are among the most attractive and interesting targets in anticancer drug discovery. The clinical relevance of HDAC inhibitors (HDACIs) is testified by four FDA-approved drugs for cancer treatment. However, one of the main drawbacks of these drugs resides in the lack of selectivity against the different HDAC isoforms, resulting in severe side effects. Thus, the identification of selective HDACIs represents an exciting challenge for medicinal chemists. HDACIs are composed of a cap group, a linker region, and a metal-binding group interacting with the catalytic zinc ion. While the cap group has been extensively investigated, less information is available about the effect of the linker on isoform selectivity. To this aim, in this work, we explored novel linker chemotypes to direct isoform selectivity. A small library of 25 hydroxamic acids with hitherto unexplored linker chemotypes was prepared. In vitro tests demonstrated that, depending on the linker type, some candidates selectively inhibit HDAC1 over HDAC6 isoform or vice versa. Docking calculations were performed to rationalize the effect of the novel linker chemotypes on biologic activity. Moreover, four compounds were able to increase the levels of acetylation of histone H3 or tubulin. These compounds were also assayed in breast cancer MCF7 cells to test their antiproliferative effect. Three compounds showed a significant reduction of cancer proliferation, representing valuable starting points for further optimization.
Preparation method of 1,4-benzdioxan-2-formic acid
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, (2018/07/30)
The invention provides a preparation method of 1,4-benzdioxan-2-formic acid. The preparation method comprises the following steps: by taking benzylodiglycidyl ether and o-halogen phenol as raw materials, performing cyclization reaction, debenzylation reaction and oxidization reaction to obtain the 1,4-benzdioxan-2-formic acid. The preparation method provided by the invention is simple in reactionprocess; as the benzylodiglycidyl ether and the o-halogen phenol are used as the raw materials for reaction, no pollutants are produced, and no-irritative and no-allergic objects are produced; compared with other existing lines, the preparation method is environmentally friendly, high in total yield and favorable for mass production; the ee value of the finally prepared 1,4-benzdioxan-2-formic acid is more than or equal to 99 percent, and the chiral purity is high.
How do reaction conditions affect the enantiopure synthesis of 2-substituted-1,4-benzodioxane derivatives?
Straniero, Valentina,Casiraghi, Andrea,Fumagalli, Laura,Valoti, Ermanno
, p. 943 - 950 (2018/05/16)
Several biologically active compounds structurally include the enantiopure 2-substituted-1,4-benzodioxane scaffold. The straightforward racemization that affects reactions involving most of the common chemical reactives is thus a crucial issue. The developing of a completely stereo-controlled synthetic route that does not affect the enantiomeric excess is consequently mandatory. It is also important to set up a reliable chiral HPLC method, able to follow the reaction, and to improve the synthetic performances. Here, we report the chiral investigation of two different synthons, we specifically evaluated the synthetic pathways that could be run in order to afford them, avoiding the racemization processes, which could normally occur in basic conditions. In addition, we developed peculiar chiral HPLC methods in order to resolve the enantiomers, define the enantiomeric excess, and fully characterize these compounds.
Crystallization-based resolution of 1,4-benzodioxane-2-carboxylic acid enantiomers via diastereomeric 1-phenylethylamides
Fumagalli, Laura,Bolchi, Cristiano,Bavo, Francesco,Pallavicini, Marco
, p. 2009 - 2011 (2016/04/20)
Unlike the diastereomeric 1-phenylethylammonium salts, the diastereomeric N-1-phenylethylamides of (S)- and (R)-1,4-benzodioxane-2-carboxylic acid show significant differences in fusibility and solubility so as to be efficiently resolved by precipitation of the less soluble diastereomer (>98% de), while chromatographic purification of the unprecipitated fraction affords the more soluble one (>99% de). Overall, 95% of the former and 80% of the latter are recovered. The hydrolysis of the two resolved amides provides the two acid enantiomers and the resolving amine in quantitative yield and with unchanged stereoisomeric purity.
Method for synthesizing doxazosin
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, (2017/01/12)
The invention discloses a method for synthesizing doxazosin and belongs to the technical field of chemical synthesis. According to the method, the doxazosin is synthesized by adopting a synthesis route, represented by formulae shown in the description, different from the conventional technologies, and thus a novel synthesis route is provided for preparing the doxazosin; and the method has the advantages of moderate conditions, simple and convenient steps and high yield, and the doxazosin can be obtained simply and efficiently.
Ultrasound-assisted synthesis and biological evaluation of 1,4-benzodioxane-2-carboxyl-amino acids and Peptides
Malipeddi, Himaja,Gowda, Visruth,Das, Moonjit
, p. 113 - 118 (2019/01/16)
A series of peptides containing 1,4-benzodioxane nucleus were attempted to synthesize by conventional as well as green techniques like microwave-assisted and sonication, using dicyclohexylcarbodiimide (DCC) as a coupling reagent and triethylamine as a bas
Synthesis and biological evaluation of a series of benzoxazole/ benzothiazole-containing 2,3-dihydrobenzo[b][1,4]dioxine derivatives as potential antidepressants
Wang, Songlin,Chen, Yin,Zhao, Song,Xu, Xiangqing,Liu, Xin,Liu, Bi-Feng,Zhang, Guisen
supporting information, p. 1766 - 1770 (2014/04/17)
A series of benzoxazole/benzothiazole-2,3-dihydrobenzo[b][1,4]dioxine derivatives (5a-5d and 8a-8j) was synthesized. Compounds were evaluated for binding affinities at the 5-HT1A and 5-HT2A receptors. Antidepressant activities of the compounds were screened using the forced swimming test (FST) and the tail suspension test (TST). The results indicated that the compounds exhibited high affinities for the 5-HT1A and 5-HT2A receptors and showed a marked antidepressant-like activity. Compound 8g exhibited high affinities for the 5-HT1A (Ki = 17 nM) and 5-HT2A (Ki = 0.71 nM) receptors; it also produced a decrease of the immobility time and exhibited potent antidepressant-like effects in the FST and TST in mice.
A facile approach to chiral 1,4-benzodioxane toward the syntheses of doxazosin, prosympal, piperoxan, and dibozane
Rouf, Abdul,Aga, Mushtaq A.,Kumar, Brijesh,Taneja, Subhash Chandra
supporting information, p. 6420 - 6422 (2013/11/19)
The process describes the concise synthesis of (R/S)-enantiomers of doxazosin, an antidepressant drug and α-adrenergic receptor antagonists like prosympal, piperoxan, and dibozane in practical yields from easily available (R)-2,3-O-cyclohexylidene-d-glyce
Chemoenzymatic synthesis of piperoxan, prosympal, dibozane, and doxazosin
Rouf, Abdul,Gupta, Pankaj,Aga, Mushtaq A.,Kumar, Brijesh,Chaubey, Asha,Parshad, Rajinder,Taneja, Subhash C.
, p. 1615 - 1623 (2013/02/22)
The synthesis of both enantiomers of 1,4-benzodioxan-2-carboxylic acid 1, a key synthetic intermediate for the therapeutic agents piperoxan, prosympal, dibozane, and doxazosin was achieved with good yields and high enantioselectivities via the Arthrobacter sp. lipase catalyzed kinetic resolution of ester (±)-17a. The influence of the co-solvents and the immobilization of the lipase upon kinetic resolution demonstrated that immobilized whole cells, in the presence of n-butanol as a co-solvent, resulted in the optimal resolution of the substrate (ee ～99%, E = 535) at 258 mmol (50 g/L) substrate concentration.
Highly efficient resolutions of 1,4-benzodioxane-2-carboxylic acid with para substituted 1-phenylethylamines
Bolchi, Cristiano,Pallavicini, Marco,Fumagalli, Laura,Marchini, Nicoletta,Moroni, Barbara,Rusconi, Chiara,Valoti, Ermanno
, p. 1639 - 1643 (2007/10/03)
The salts of (S)- and (R)-1,4-benzodioxane-2-carboxylic acid with eight (S)-1-arylethylamines were prepared. The determination of their melting points and of their solubilities in alcohol solvents revealed large differences between the diastereomeric benzodioxanecarboxylates of (S)-1-(p-nitrophenyl)ethylamine and of (S)-1-(p-methylphenyl)ethylamine. Therefore, these latter amines were selected to resolve (±)-1,4-benzodioxane-2-carboxylic acid by diastereoselective crystallization finding that both of them display a very high resolution ability for such a substrate, which contrasts with the null efficiency of unsubstituted 1-phenylethylamine. These results are consistent with DSC evidences, which indicated that the two successfully resolved diastereomeric systems are binary mixtures exhibiting a eutectic with a high content of the more soluble diastereomeric salt. The new procedures can advantageously replace the two resolutions we had previously reported, that of the same acid with dehydroabietylamine and that of glycerol acetonide, a precursor of 1,4-benzodioxane-2-carboxylic acid, with 1-phenylethylamine.
